Enterohepatic Circulation

Bile acids travel in the bile through the liver, biliary tree, intestines, and the portal venous circulation to return to the liver, thereby recovering 95% of bile acids, with the other 5% passing in stool. Hepatocytes secrete bile acids through a rate-limiting, ATP-dependent process via a bile salt export pump. Approximately 600 to 750 mL of bile is produced daily. Hormones, such as secretin, cholecystokinin (CCK), and gastrin increase bile flow primarily by promoting active secretion of chloride-rich fluid in the bile ducts.

Gallbladder Function

The main functions of the gallbladder are to concentrate and store bile during the fasting state and deliver bile into the duodenum when needed. Bile reenters the distal bile duct and is secreted into the duodenum in response to a meal. The gallbladder mucosa is unique in that it has the greatest absorptive capacity per unit of any structure in the body, but the gallbladder itself has a limited storage capacity of approximately 50 mL; thus the bile it can store is made more effective through the process of concentration.

The gallbladder’s mucosa secretes mucous glycoproteins and hydrogen ions. Mucous glycoproteins are actively secreted from the mucosal glands in the gallbladder neck and cystic duct. The resultant mucous barrier protects the gallbladder epithelium from the detergent effect of concentrated bile salts. The transport of hydrogen ions by the gallbladder epithelium leads to a decrease in bile pH through an active sodium-exchange mechanism. Acidification of bile in the gallbladder promotes calcium solubility, thereby preventing its precipitation as calcium salts and subsequent gallstone formation. The gallbladder’s normal acidification process lowers the pH of hepatic bile from 7.5 to 7.8 down to 7.1 to 7.3.⁷

Biliary Motility

Gallbladder filling is facilitated through tonic contraction of the ampullary sphincter, which maintains a constant pressure in the common bile duct (CBD) (10 to 15 mm Hg). There are periods of gallbladder filling flanked by brief periods of partial emptying (10% to 15% of its volume) of concentrated bile. These emptying periods are coordinated with each passage of chyme through the duodenum via the migrating myoelectric complex (MMC) and the hormone motilin. Following a meal, the release of stored bile from the gallbladder requires coordination of both gallbladder contraction and sphincter of Oddi relaxation. CCK is released from the duodenal mucosa in response to a meal, and this hormone serves as a major stimulus for gallbladder contraction. Following a meal, the gallbladder releases 50% to 70% of its contents within 30 to 40 minutes. Gallbladder refilling then occurs gradually over the next 60 to 90 minutes. Many other hormonal and neural pathways are also necessary for the coordinated action of the gallbladder and sphincter of Oddi. Dysmotility of the gallbladder increases the time bile dwells in the gallbladder, and along with calcium precipitation, plays a central role in the pathogenesis of gallstones.⁸

Sphincter of Oddi

The human sphincter of Oddi is a complex structure that is functionally independent from the duodenal musculature. Endoscopic manometric studies demonstrate that the sphincter of Oddi creates a high-pressure zone between the bile duct and the duodenum, which regulates the flow of bile and pancreatic juice into the duodenum while preventing regurgitation of duodenal contents into the biliary tract. Through this action, a higher luminal pressure is maintained in the biliary tract than in the duodenal lumen.

Both neural and hormonal factors influence the sphincter of Oddi. In humans, sphincter of Oddi pressure and phasic wave activity diminish in response to CCK. Thus, sphincter pressure relaxes after a meal, allowing the passive flow of bile into the duodenum. During fasting, high-pressure phasic contractions of the sphincter of Oddi persist through all phases of the MMC. Results of animal studies demonstrate that sphincter of Oddi phasic waves do vary with the MMC, permitting partial gallbladder emptying and increasing bile flow during phase III of the MMC; a mechanism which may serve to limit accumulation of biliary crystals during fasting.⁹ Neurally mediated reflexes link the sphincter of Oddi with the gallbladder and stomach to coordinate the flow of bile and pancreatic juice into the duodenum. The cholecystosphincter of Oddi reflex allows the sphincter to relax as the gallbladder contracts. Similarly, antral distention causes both gallbladder contraction and sphincter relaxation.

GALLSTONES

Ten to 20% of adults in the United States will be affected by gallstones during their lifetime.¹⁰ The vast majority of people with gallstone will have asymptomatic disease diagnosed incidentally via imaging (ultrasound [US], computed tomography [CT], or magnetic resonance imaging [MRI]) for other health problems. It is estimated that 2% to 3% per year of those with known gallstones will develop symptoms¹¹ and 1% to 2% will develop more complex problems such as cholecystitis, pancreatitis, or cholangitis annually.¹² Gallstones represent a failure to maintain certain biliary solutes, primarily cholesterol and calcium salts, in a solubilized state, and can form in the gallbladder and less commonly in the bile ducts.

Gallstone Formation

1, 2 The gallbladder fills with hepatic bile during tonic contraction of the ampullary sphincter. Following a meal, the duodenum releases the gut peptide CCK, which stimulates gallbladder emptying. Fifty to 70% of the gallbladder contents are forced into the duodenum and then refilling gradually happens within the next 60 to 90 minutes.¹³ The combination of hepatic bile acidification and concentration in the gallbladder, by 5 to 10-fold, enhance calcium solubility; however, the secretion of mucous glycoproteins to protect the mucosa from bile salts serves as a nidus for cholesterol stone formation. An important biliary precipitate in gallstone pathogenesis is biliary “sludge,” which refers to a mixture of cholesterol crystals, calcium bilirubinate granules, and a mucin gel matrix. Biliary sludge has been observed clinically in prolonged fasting states or with the use of long-term total parenteral nutrition (TPN). Both of these conditions are also associated with gallstone formation. The finding of macromolecular complexes of mucin and bilirubin, similar to biliary sludge in the central core of most cholesterol gallstones, suggests that sludge may serve as the nidus for gallstone formation.

Gallstone Types

3 Gallstones are classified by their cholesterol content as either cholesterol or pigment stones. Pigment stones are further classified as either black or brown (Fig. 61-1). In most American populations, 70% to 80% of gallstones are cholesterol stones and the others are black pigment stones.

Cholesterol Gallstones

Pure cholesterol gallstones are uncommon, as most have a core of calcium salts (90%). The pathogenesis of cholesterol gallstones involves four key factors: (a) cholesterol supersaturation in bile, (b) crystal nucleation, (c) gallbladder dysmotility, and (d) gallbladder absorption/secretion.

Cholesterol Supersaturation. The key to maintaining cholesterol in solution is the formation of micelles, a bile salt–phospholipid–cholesterol complex, and cholesterol–phospholipid vesicles (Fig. 61-2). Present theory suggests that in states of excess cholesterol production, these large vesicles may exceed their capability to transport cholesterol and crystal precipitation may occur. Cholesterol solubility depends on the relative concentration of cholesterol, bile salts, and phospholipid. By plotting the percentages of each component on triangular coordinates, the micellar zone in which cholesterol is completely soluble can be demonstrated (Fig. 61-3). In the area above the curve, bile is supersaturated with cholesterol and precipitation of cholesterol crystals can occur.

Cholesterol Crystallization. Cholesterol supersaturation does not always result in stone formation. As bile is concentrated in the gallbladder, a net transfer of phospholipids and cholesterol from vesicles to micelles occurs. The phospholipids are transferred more efficiently than cholesterol, leading to cholesterol enrichment in the vesicles. These cholesterol-rich vesicles aggregate to form large multilamellar liquid vesicles that then precipitate cholesterol monohydrate crystals. Several pronucleating factors including mucin glycoproteins, immunoglobulins, and transferrin accelerate the precipitation of cholesterol in bile.

Gallbladder Motility. For gallstones to cause clinical symptoms, they must obtain a size sufficient to produce mechanical injury to the gallbladder or obstruction of the biliary tree. Growth of stones may occur in two ways: (a) progressive enlargement of individual crystals or stones by deposition of additional insoluble precipitate at the bile–stone interface, or (b) fusion of individual crystals or stones to form a larger conglomerate. Poor gallbladder motility increases the dwell time of bile in the gallbladder, further promoting stone formation. Clinical conditions associated with reduced gallbladder motility include prolonged fasting, long-term TPN administration, surgical vagotomy, diabetes mellitus, and supratherapeutic levels of somatostatin resulting from either somatostatin-producing tumors or in patients receiving long-term somatostatin therapy.

Gallbladder Absorption/Secretion. Alterations in sodium, chloride, bicarbonate, and water absorption may alter the milieu for cholesterol saturation and crystal formation as well as for calcium precipitation.¹⁴

Pigment Gallstones

Pigment gallstones are classified as either brown or black pigment stones.

Brown Pigment Stones. These stones are composed of calcium bilirubinate, fatty acid soaps (calcium palmitate and calcium stearate), cholesterol, and mucinous glycoproteins (products of bacterial biofilms). They are earthy in texture and are typically found in the intrahepatic and extrahepatic bile ducts (as opposed to the gallbladder) in states of increased bile duct stasis, such as sclerosing cholangitis, congenital biliary cystic disease, chronic biliary strictures, chronic pancreatitis, duodenal diverticula, and infections with bacteria or biliary parasites. East Asian populations are particularly at risk of brown stone formation due to susceptibility to oriental cholangiohepatitis (recurrent pyogenic cholangitis). In this condition, bacteria produce a biofilm rich in glucuronidase, which hydrolyses conjugated bilirubin to free bilirubin. Free bilirubin precipitates when mixed with calcium.

In these settings, bacteria-producing slime and bacteria containing the enzyme glucuronidase cause enzymatic hydrolysis of soluble conjugated bilirubin glucuronide to form free bilirubin, which then precipitates with calcium leading to stone formation.

Black Pigment Stones. These stones form primarily in the gallbladder in sterile bile and are associated with advanced age, chronic hemolysis, alcoholism, cirrhosis, pancreatitis, and total parenteral nutrition, and are typically tarry. These stones are usually not associated with infected bile and are located almost exclusively in the gallbladder.

INDICATIONS FOR CHOLECYSTECTOMY

Asymptomatic Patients

4 Given that the large majority of individuals with gallstones are asymptomatic and have no associated complications, most patients can be managed expectantly without surgical intervention. Prophylactic cholecystectomy may, however, be indicated in certain circumstances (Table 61-2). Patients who have a higher risk of cancer in the setting of gallbladder disease, such as Native Americans, presence of large gallstones (>2.5 cm), or calcification of gallbladder wall (“porcelain gallbladder”) are commonly offered prophylactic cholecystectomy. Patients who are more likely to have recurrent symptoms or complications secondary to gallstone disease may also undergo prophylactic cholecystectomy; examples of these conditions include hereditary spherocytosis, sickle cell disease, other hemoglobinopathies, the bariatric patients, and pediatric patients. Finally, some clinicians argue that organ transplant patients with gallstones should undergo pretransplant prophylactic cholecystectomy given the possible higher risk of developing complicated gallstone disease due to chronic immunosuppression.

Patients with asymptomatic gallstones who are not offered a cholecystectomy, or choose not to undergo an operation, can be managed with other therapies. In patients with small gallstones (<5 mm) oral dissolution therapy with bile salts may be utilized.²² Ursodeoxycholic acid (ursodiol) appears to work by dissolving cholesterol crystals and decreasing hepatic secretion of biliary cholesterol thereby decreasing the number of stones. It is also thought that this would decrease the number of colic attacks. Unfortunately, the majority of stones recur (>50% at 5 years) and in a prospective randomized study of 177 patients from the Netherlands, a country that has a long waiting list for elective biliary procedures, ursodiol did not decrease the number of attacks nor gallstone-related complications during the waiting period for cholecystectomy.²³

An additional therapy, although not commonly employed, is extracorporeal shock wave lithotripsy (ESWL). This therapy uses energy (“shock”) waves, produced by different methods depending on the generator technology, to dissolve stones. ESWL can dissolve small calculi or decrease the size of larger calculi and make them potentially extractable by endoscopic or percutaneous techniques, if in the CBD or distal cystic duct, or dissolvable by oral therapy if present in the gallbladder. It is a relatively safe procedure with rare complications, including: hematoma (biliary or otherwise), bowel perforation, and necrotizing pancreatitis.²⁴

Symptomatic Patients

It is estimated that 2% to 3% per year of those with known gallstones will develop symptoms¹¹ and 1% to 2% will develop more complex problems (such as cholecystitis, pancreatitis, or cholangitis) annually (Table 61-3).¹² Those who develop symptoms will most often have biliary colic, or right upper quadrant (RUQ) pain, which will often recur. Biliary colic will often last for several hours after onset before subsiding. Biliary colic develops secondary to intermittent impaction of gallstones at the gallbladder neck as the gallbladder contracts in order to deliver its contents into the CBD. In more than 50% of patients it occurs following a fatty meal. Biliary colic can be associated with belching, bloating, and even nausea or emesis. Over time this intermittent obstruction leads to increased tension in the gallbladder wall and more chronic pain and inflammation known as chronic cholecystitis.

COMPLICATED GALLSTONE-RELATED DISEASE

Complicated gallstone-related disease (acute cholecystitis [AC], choledocholithiasis, and associated consequences of gallstone pancreatitis or cholangitis) will occur in 0.3% to 3% of patients per year.²⁵ These complications increase the morbidity and potential mortality of patients with gallstones.

Acute Cholecystitis

AC develops when a gallstone(s) lodges in the gallbladder neck (infundibulum) obstructing bile flow into the CBD. This obstruction leads to biliary stasis, gallbladder wall edema, venous obstruction, and in extreme cases, eventual arterial obstruction causing necrosis of the gallbladder wall. Its course can range from mild pain with fevers to frank sepsis secondary to perforation or development of emphysematous/gangrenous cholecystitis. Clinically, patients present in a similar manner to those with biliary colic; however the pain is constant, unrelenting, and often associated with fevers, tachycardia, and a leukocytosis. The diagnosis is typically made with a thorough history and physical examination, in which the patient may present with midepigastric or RUQ pain, as well as, localized peritoneal irritation. Murphy’s sign, which is defined by cessation of inspiration secondary to pain, due to the presence of an inflamed gallbladder during deep abdominal palpation at the midclavicular line of the RUQ, is pathognomonic for AC.

Imaging and Diagnosis

A variety of imaging tests can be used when evaluating the patient with AC, each of which have different strengths and weaknesses, and serve as an adjunct to a thorough history and physical examination.

Ultrasound (US) uses oscillating sound waves to measure differences in tissue densities and interfaces between liquids and solids and is the backbone of imaging for gallstone disease (Fig. 61-4). The primary advantages of US are that it is readily available, quickly performed, and avoids ionizing radiation. The main disadvantage is that it is user-dependent, and technique and experience are therefore quite important.²⁶ AC can be diagnosed by various US criteria, with the higher number of criteria met on US examination, the more likely for cholecystitis to be present. These criteria include gallbladder wall thickening >5 mm, pericholecystic fluid, gallstones, and a positive sonographic Murphy sign characterized by pain and cessation of inspiration when the probe is pressed over the gallbladder. A 2012 meta-analysis by Kiewiet et al.²⁷ which included 26 studies with 2,847 patients, evaluated the role of US as a tool to diagnose AC, and reported a sensitivity of 81% and specificity of 83% with the comparison being against surgical pathologic findings in the majority of patients.

HIDA scan (biliary scintigraphy) first came into use in the late 1970s.²⁸ The injectable radioactive dye (derivatives of technetium and iminodiacetic acid) used is preferentially taken up by the liver and excreted into the bile and should fill both the CBD and gallbladder if there is free flow through the entire biliary system. A HIDA scan is considered positive for AC if there is lack of visualization of the gallbladder due to cystic duct occlusion from gallstones which does not allow the radioactive tracer to enter the gallbladder (Fig. 61-5). The overall sensitivity for AC of a HIDA scan is 95% to 98% with a specificity of >90%.^27,28 A false-positive HIDA scan can occur in various situations, including consumption of a recent meal (the gallbladder is contracted due to CCK), prolonged fasting (the gallbladder has concentrated thick bile which acts as a mechanical obstruction to entrance of the tracer), chronic cholecystitis, or the presence of underlying hepatobiliary disease.

Limitations of HIDA scans are that it is not always readily available, especially after hours, and require exposure to ionizing radiation; thus, most clinicians will begin with US and then use HIDA to clarify equivocal US results. Several studies have looked at the utility of adding HIDA to US in the case of diagnostic dilemma, but the combined modalities do not appear to add sensitivity or specificity for detection of AC, although they may provide additional morphologic information.^29–31

CT scans are typically less helpful for diagnosing uncomplicated gallstone disease, as most gallstones (85%) are not radiopaque. CT scans are limited in their ability of evaluating the CBD and identifying an obstruction of the cystic duct, which is a prerequisite for the diagnosis of AC.^26,32–34 They have been shown to be less sensitive and specific than US.³² CT scans can be helpful, however, in evaluating patients for complications of AC (Fig. 61-4). Gangrenous cholecystitis, which is the most common AC complication, occurs in up to 38% of patients with AC. Gallbladder perforation and abscess formation can be seen in up to 8% to 12% of AC cases. A CT scan can detect a defect in the gallbladder wall in 53% of patients with early perforation whereas US cannot easily delineate a mural defect, unless large, although both will likely help detect the resulting abscess formation (Fig. 61-6).

MRI has only been evaluated in small studies in the setting of AC. Its sensitivity and specificity are similar to that of US (approximately 80% to 85% for both). MRI is useful for evaluation of the biliary tree and to assess for the presence of choledocholithiasis; however, it can overestimate the presence of gallbladder wall inflammation (Fig. 61-4). Advancements in MRI protocols employing unique tracers that are taken up and excreted in the biliary tree similar to iminodiacetic acid compounds, such as Eovist, are currently under investigation.³⁵ Ultimately, the current cost and availability of MRI machines make it of limited use for the diagnosis of AC.

Treatment

The treatment of AC can consist of medical or surgical therapies and the correct treatment modality will depend on the individual clinical scenario. The medical treatment of AC involves nothing per os, parenteral hydration, and antibiotics until the patient’s clinical examination improves and pain resolves. The diet is then slowly advanced and the patient is kept on a low-fat diet until cholecystectomy is performed. Despite symptom resolution, the patient should undergo an interval cholecystectomy, as the likelihood of a second biliary-related complication is high. Surgical therapy consists of either a laparoscopic or open cholecystectomy, or placement of a cholecystostomy tube in combination with medical therapy.

5 Cholecystectomy. Cholecystectomy is considered standard therapy for patients with symptomatic gallstones and AC. With regard to the surgical treatment of AC, the discussion in the literature has been the timing of the cholecystectomy – early versus delayed. Early cholecystectomy removes the pathologic source, usually within the first 72 hours of presentation. Certain clinicians advocate for delayed cholecystectomy to allow the acute inflammatory response to resolve potentially making the surgery safer with fewer complications and morbidity, such as bile duct injuries, bleeding, and conversion from laparoscopic to open procedure.

6 A 2006 meta-analysis showed no significant differences in patient outcomes between early and delayed surgeries with respect to bile duct injuries, bleeding complications, laparoscopic-to-open conversion, postoperative infection, and patient death.³⁶ It was noted that over 23% of delayed patients presented with complications requiring emergent cholecystectomy. Furthermore, total hospital stay, including the index admission and subsequent admissions for biliary complications and later cholecystectomy, was significantly shorter for early cholecystectomy, leading to a decreased cost to the patient and system.

Early has also been somewhat of a misnomer, as traditionally this early approach has consisted of performing a cholecystectomy within 72 hours of the onset of symptoms. A Cochrane review in 2006,³⁷ which included 6 randomized trials with 488 patients, compared early (within 7 days of presentation) to late (>6 weeks after initial treatment) cholecystectomy and found similar results to the above meta-analysis with no increase in terms of complications and outcomes. Multiple studies demonstrate that early should be within the index admission and the 72-hour limit is not as much a steadfast rule given improved skills of surgeons with laparoscopic surgery and the understanding that surgery delayed to a different admission could potentially lead to worse complications.

A recent study from Italy seems to confirm these data. Patients (n = 316) were enrolled in a prospective study³⁸ to assess the benefit of immediate cholecystectomy during the index admission or delayed surgery after at least 4 weeks. As with the other studies, the complication profiles were no different between the two groups; however, the subgroup analysis within the early intervention group showed that immediate surgery on admission or early surgery within 48 hours was associated with shorter operative time, similar conversion and complication rates, and shorter hospital stay. Within the delayed group, 26% required rehospitalization and 37% required urgent reevaluation prior to planned surgery.

Percutaneous Cholecystostomy. In the otherwise healthy patient with AC, laparoscopic cholecystectomy should be considered the therapy of choice during the index hospitalization. However, in the elderly patient with poor performance status, multiple comorbidities, or for the extremely ill patient in the intensive care unit, the underlying medical status may impact increased perioperative risk and therefore preclude surgical intervention. Percutaneous cholecystostomy (PC) may be employed as a bridge or final therapy in such patients. This procedure was first described in the 1980s by Radder et al.³⁹ and involves the placement of a percutaneous transhepatic drain into the gallbladder (Fig. 61-7). The transhepatic approach has remained the method of choice to reduce intraperitoneal bile leak in case of tube dislodgement. Use of this approach has grown over 500% since 1994, along with the field of interventional radiology.⁴⁰ Typically, rapid patient improvement is seen following decompression in combination with antibiotics tailored to bacterial isolates. In most patients, an interval cholecystectomy will be performed 6 weeks or more after the drain is placed. Removing the drain alone is usually not sufficient, as the cystic duct obstruction is typically still present. If Bile is draining from the catheter, then it may be possible to remove the catheter after 6 weeks without removing the gallbladder in patients with questionable fitness for surgery.

Acalculous Cholecystitis

Acute acalculous cholecystitis (AAC) represents 12% of all cases of AC with the incidence being significantly higher in intensive care unit patients.⁴¹ AAC is associated with increased bile stasis and therefore decreased gallbladder emptying, which typically occurs in the setting of severe illness with multiple contributing mediators, such as the inflammatory response, total parenteral nutrition, and high-dose narcotics. The diagnosis of ACC requires a high index of clinical suspicion, as patients are often critically ill and unable to communicate symptoms. The potential consequences of late diagnosis are considerable, with gallbladder ischemia and progression to gangrene and eventual perforation resulting in a mortality rate of up to 30%.⁴² Diagnosis may be made using bedside ultrasonography following similar criteria as used for acute calculous cholecystitis, with the exception of lack of calculi. The sensitivity of US in this setting ranges from 50% to 100% with a specificity of 90% to 94%. HIDA scan with morphine amplification can be used to increase bile secretory pressure and allow bile to reflux through a contracted gallbladder neck, thereby decreasing false-positive rates, providing sensitivity rates of 67% to 100% and specificity rates of 69% to 100%.⁴¹

US remains the initial test of choice, as it is relatively inexpensive, and may be performed at the bedside in the ICU. However, a negative US in a patient with a high clinical suspicion for AAC may benefit from a HIDA scan to improve diagnostic yield.⁴³ Treatment of AAC is either a cholecystectomy in the stable patient or more likely, PC tube placement in the critically ill, unstable patient.

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